Sensorimotor adaptation in Parkinson's disease: evidence for a dopamine dependent remapping disturbance.

Sensorimotor adaptation is thought to involve a remapping of the kinematic and kinetic parameters associated with movements performed within a changing environment. Patients with Parkinson's disease (PD) are known to be affected on this type of learning process, although the specific role of dopamine depletion in these deficits has not yet been elucidated. The present study was an attempt to clarify whether dopamine depletion in PD may directly affect the capacity to internally reorganize the visuomotor remapping of a distorted environment. Fourteen PD patients were tested twice, while they were treated and while they were withdrawn from their regular levodopa treatment. Fourteen control subjects were also enrolled and tested twice. Two parallel forms of the Computed Mirror Pointing Task (CMPT), requiring making a reaching movement in a visually transformed environment (mirror inversion), were administered to each participant. Each of them had to perform 40 trials at each of the 2 testing sessions. At each trial, sensorimotor adaptation was evaluated by the initial direction angle (IDA), which reflects the direction of movement before any visually guided readjustment. Results revealed no IDA difference at baseline, between control subject and PD patients, whether they were treated or not. In all group, IDA values at that time were large, reflecting a tendency to make movements according to the real life visuomotor mapping (based on the natural direct vision). However, striking differences appeared during sensorimotor learning, in that IDA reduction along trials was poorer in patient not treated with levodopa than both control subjects and the same PD patient treated with levodopa. No difference was observed between the treated PD patients and control subjects. Given that IDA is thought to reflect the internal representation of the visuomotor mapping, it is concluded that dopamine depletion in PD would affects sensorimotor adaptation, in that it facilitates old and poorly adapted movements (real life mapping), instead of new and more adapted ones (mirror transformed mapping).

Raclopride-induced motor consolidation impairment in primates: role of the dopamine type-2 receptor in movement chunking into integrated sequences.

Results obtained in patients with schizophrenia have shown that antipsychotic drugs may induce motor learning deficits correlated with the striatal type-2 dopamine receptors (D(2)R) occupancy. Other findings suggest that the role of the striatum in motor learning could be related to a process of "chunking" discrete movements into motor sequences. We therefore hypothesized that a D(2)R blocking substance, such as raclopride, would affect motor learning by specifically disrupting the grouping of movements into sequences. Two monkeys were first trained to perform a baseline-overlearned sequence (Seq. A) drug free. Then, a new sequence was learned (Seq. B) and the overlearned sequence was recalled OFF-drug (Seq. A recall OFF-drug). The effect of raclopride was then assessed on the learning of a third sequence (Seq. C), and on the recall of the overlearned sequence (Seq. A recall ON-drug). Results showed that performance related to the overlearned sequence remained the same in the three experimental conditions (Seq. A, Seq. A recall OFF-drug, Seq. A recall ON-drug), whether the primates received raclopride or not. On the other hand, new sequence learning was significantly affected during raclopride treatment (Seq. C), when compared with new sequence learning without the effect of any drug (Seq. B). Raclopride-induced disturbances consisted in performance fluctuations, which persisted even after many days of trials, and prevented the monkeys from reaching a stable level of performance. Further analyses also showed that these fluctuations appeared to be related to monkeys' inability to group movements into single flowing motor sequences. The results of our study suggest that dopamine is involved in the stabilization or consolidation of motor performances, and that this function would involve a chunking of movements into well-integrated sequences.

Dopamine-receptor stimulation: biobehavioral and biochemical consequences.

The MPTP monkey is a well-characterized animal model of parkinsonism and provides an exceptional tool for the study of dyskinesias induced by dopamine-like agents. Several such agents have been tested during the past 15 years, and it has been found that the duration of action of these compounds is the most reliable variable with which to predict their dyskinesiogenic profile. It is proposed that L-dopa-induced dyskinesias represent a form of pathological learning caused by chronic pulsatile (nonphysiological) stimulation of dopamine receptors, which activates a cascade of molecular and biochemical events. These events include defective regulation of Fos proteins that belong to the deltaFosB family, increased expression of neuropeptides, and defective GABA- and glutamate-mediated neurotransmission in the output structures of the basal ganglia.

Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease.

The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinson's disease.

Neostriatal mechanisms in Parkinson's disease.

Normal motor function is dependent on the highly regulated synthesis and release of dopamine (DA) by neurons projecting from substantia nigra to corpus striatum. Cardinal symptoms of Parkinson's disease (PD) arise as a consequence of a deficiency in striatal DA due to the progressive degeneration of this neuronal system. Under such circumstances, the subunit composition and/or phosphorylation state of glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype expressed on the dendritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic transmission, significant differences exist between the normally functioning DA system and the restoration of function provided by standard levodopa therapy. The nonphysiologic stimulation of DA receptors on striatal spiny neurons associated with current levodopa regimens now appears to contribute to the motor response complications that ultimately affect most parkinsonian patients. Current evidence suggests that alterations in signaling systems linking dopaminergic and glutamatergic receptors within these GABAergic efferent neurons induce NMDA receptor modification. Functionally, the resultant long-term change in glutamatergic synaptic efficacy leads to alterations in spiny neuron output, favoring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimulation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transduction components or glutamate receptor sensitivity could ultimately prove safer and more effective for the treatment of all stages of PD.

AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys.

OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. BACKGROUND: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. METHODS: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. RESULTS: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). CONCLUSIONS: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

Short-term effects of high-dose 17beta-estradiol in postmenopausal PD patients: a crossover study.

OBJECTIVE: To examine the effect of 17beta-estradiol on the severity of the cardinal signs of PD in postmenopausal women. BACKGROUND: Although the impact of estrogens on the manifestations of PD has not been subjected to rigorous study, their use is generally thought to be associated with a detrimental antidopaminergic effect. METHODS: A double-blind, placebo-controlled, two-arm crossover study of high-dose transdermal 17beta-estradiol was conducted in eight postmenopausal women with mild to moderate PD, all but one of whom exhibited levodopa-induced dyskinesias. Patients were randomized initially to either hormonal treatment or placebo for 2 weeks, followed by a 2-week washout period, and then another 2-week crossover treatment period. Active treatment employed four skin patches each releasing 0.1 mg of estradiol daily, replaced every 2 to 3 days. RESULTS: After 10 days of treatment a significant reduction was observed in the antiparkinsonian threshold dose of IV levodopa. Mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17beta-estradiol treatment compared with placebo. No worsening in "on" time or motor ratings with estrogen treatment was documented. CONCLUSIONS: 17beta-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Standard postmenopausal replacement therapy with transdermal 17beta-estradiol is likely to be well tolerated by many female parkinsonian patients.

Continuous or pulsatile chronic D2 dopamine receptor agonist (U91356A) treatment of drug-naive 4-phenyl-1,2,3,6-tetrahydropyridine monkeys differentially regulates brain D1 and D2 receptor expression: in situ hybridization histochemical analysis.

The effect of a chronic D2 dopamine receptor agonist (U91356A) treatment on dopamine receptor gene expression in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys was investigated using quantitative in situ hybridization histochemistry. U91356A was administered to MPTP-monkeys for 27 days in a pulsatile (n=3) or continuous (n=3) schedule. Animals treated in a pulsatile mode showed progressive sensitization and developed dyskinesia; whereas with the continuous mode behavioural tolerance was observed but no dyskinesia developed. Untreated MPTP as well as naive control animals were also studied. The efficacy and uniformity of the MPTP effect was assessed by measures of dopamine concentrations by high performance liquid chromatography with electrochemical detection in the relevant brain areas. D1 and D2 receptor messenger RNAs levels were examined by in situ hybridization histochemistry using human complementary RNA probes. Intense specific labelling for D1 and D2 receptor messenger RNAs was measured in the caudate and putamen with a rostrocaudal gradient for D2 receptors and a lower density in the cortex for D1 receptors messenger RNA. D1 receptor mRNA levels in rostral striatum and cortex decreased whereas D2 receptor messenger RNA in caudal striatum increased in MPTP-monkeys compared to control animals. Continuous administration of U91356A reversed the MPTP-induced increase of D2 receptor messenger RNA, whereas the pulsatile administration did not significantly correct these messenger RNA changes. U91356A treatment whether continuous or pulsatile partially corrected the D1 receptor messenger RNA lesion-induced decrease in the striatum, whereas no correction was observed in the cortex. All MPTP-monkeys were extensively and similarly denervated suggesting that the D1 and D2 receptor expression changes following U91356A administration were treatment related. Our data show a lesion-induced imbalance of D1 (decrease) and D2 (increase) receptor messenger RNAs in the striatum of MPTP-monkeys. The response of these receptors to D1 agonist treatment showed receptor selectivity and was influenced by the time-course of drug delivery. Hence chronic continuous but not pulsatile administration of U91356A reversed the striatal D1 receptor messenger RNA increase.

L-DOPA regulates glutamate decarboxylases mRNA levels in MPTP-treated monkeys.

The effect of dopaminergic denervation, alone or followed by chronic intermittent L-DOPA administration, on the levels of mRNAs encoding for the two isoforms of the GABA-synthesizing enzyme, glutamate decarboxylase (GAD65 and GAD67), were measured by in-situ hybridization in the caudate and putamen of macaque monkeys. When compared to control monkeys, the level of GAD67 mRNA was increased in the putamen and caudate of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. On the other hand, GAD65 mRNA labeling in MPTP-treated monkeys was not significantly different from the controls. In MPTP-treated monkeys that received L-DOPA, a significant increase in both GAD67 and GAD65 mRNA levels was measured in the putamen when compared to control or MPTP-treated monkeys. The results suggest that the dyskinetic effect of L-DOPA is paralleled by an increased GABAergic activity in the striatum.

Preproenkephalin mRNA expression in the caudate-putamen of MPTP monkeys after chronic treatment with the D2 agonist U91356A in continuous or intermittent mode of administration: comparison with L-DOPA therapy.

The effect of chronic treatment with the D2 dopamine agonist U91356A or L-DOPA therapy on the regulation of preproenkephalin (PPE) mRNA was investigated in the caudate-putamen of previously drug-naive cynomolgus monkeys Macaca fascicularis rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In MPTP monkeys, pulsatile treatment with either L-DOPA or U91356A relieved parkinsonian symptoms but caused progressive sensitization to treatment and, as expected, induced choreic dyskinesias. In contrast, U91356A given in a continuous mode led to partial behavioral tolerance without appearance of dyskinesias. Using in situ hybridization histochemistry, lesioning was shown to produce elevation of PPE mRNA levels in the lateral and medial parts of the putamen and in the lateral part of the caudate nucleus compared to control animals at the three rostrocaudal regions analyzed. In general, no change of PPE mRNA levels were observed in the medial caudate after MPTP lesioning with or without L-DOPA or U91356A treatments in the three rostrocaudal regions measured except for an increase in the caudal part of L-DOPA-treated MPTP monkeys. In the putamen and lateral caudate nucleus, elevated PPE mRNA expression by MPTP generally was not corrected (or only partially corrected) by chronic L-DOPA treatment except for the rostral medial putamen where correction to control values was observed. In general, pulsatile administration of U91356A partially corrected the lesion-induced elevation of PPE mRNA levels in the putamen and lateral caudate nucleus whereas the correction was more pronounced and widespread when MPTP monkeys received the continuous administration of this drug. These results indicate that the mode of administration of a D2 dopamine receptor agonist, such as U91356A, although at a roughly equivalent dosage influences the extent of inhibition of the expression of PPE in the denervated striatum of monkeys. In addition, the general lack of correction of the MPTP-induced increase of PPE mRNA in the striatum of L-DOPA-treated monkeys compared to the decreases observed with the D2 agonist treatments suggest that the D1 agonist component of L-DOPA therapy opposes the D2 agonist activity. Hence, D1 receptor agonist activity would stimulate PPE mRNA expression whereas D2 receptor agonists inhibit the expression of this peptide. Increases in PPE expression in the striatum may be implicated in the induction of dyskinesias since both groups of treated MPTP monkeys displaying dyskinesias had elevated striatal PPE mRNA levels whereas the MPTP monkeys with the lowest striatal PPE mRNA levels developed tolerance without dyskinesias.

Chronic D1 and D2 dopaminomimetic treatment of MPTP-denervated monkeys: effects on basal ganglia GABA(A)/benzodiazepine receptor complex and GABA content.

The effect of various chronic dopaminergic treatments in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys on the brain gamma-aminobutyric acid type A (GABA(A)) /benzodiazepine receptor complex and GABA content was investigated in order to assess the GABAergic involvement in dopaminomimetic-induced dyskinesia. Three MPTP monkeys received for one month pulsatile administrations of the D1 dopamine (DA) receptor agonist SKF 82958 whereas three others received the same dose of SKF 82958 by continuous infusion. A long acting D2 DA receptor agonist, cabergoline, was given to another three animals. Untreated MPTP as well as naive control animals were also included. Pulsatile SKF 82958 relieved parkinsonian symptoms but was also associated with dyskinesia in two of the three animals whereas animals treated continuously with SKF 82958 remained as untreated MPTP monkeys. Chronic cabergoline administration improved motor response with no persistent dyskinesia. MPTP treatment induced a decrease of 3H-flunitrazepam binding in the medial anterior part of caudate-putamen and an increase in the internal segment of globus pallidus (GPi) which was in general unchanged by pulsatile or continuous SKF 82958 administration. Throughout the striatum, binding of 3H-flunitrazepam remained reduced in MPTP monkeys treated with cabergoline but was not significantly lower than untreated MPTP monkeys. Moreover, cabergoline treatment reversed the MPTP-induced increase in 3H-flunitrazepam binding in the GPi. GABA concentrations remained unchanged in the striatum, external segment of globus pallidus and GPi following MPTP denervation. Pulsatile but not continuous SKF 82958 administration decreased putamen GABA content whereas cabergoline treatment decreased caudate GABA. No alteration in GABA levels were observed in the GPe and GPi following the experimental treatments. These results suggest that: (1) D2-like receptor stimulation with cabergoline modulates GABA(A) receptor density in striatal subregions anatomically related to associative cortical afferent and (2) the absence of dyskinesia in dopaminomimetic-treated monkeys might be associated with the reversal of the MPTP-induced upregulation of the GABA(A)/benzodiazepine receptor complex in the Gpi.

Opposite rotation induced by dopamine agonists in rats with unilateral lesions of the globus pallidus or substantia nigra.

Normal rats with a unilateral ibotenic acid lesion of substantia nigra pars reticulata (SNR, n = 12) or globus pallidus (GP, n = 12) were challenged systemically with the mixed dopaminergic agonist apomorphine (0.5 and 1.5 mg/kg) and the indirect acting d-amphetamine (1.5 mg/kg). The low dose of apomorphine produced a weak contralateral rotation only in the SNR-lesioned group, which showed an intense ipsilateral rotation following the administration of the higher dose. GP-lesioned rats also showed ipsilateral rotation after the high dose of apomorphine. d-Amphetamine produced ipsilateral rotation in GP-lesioned rats, contrasting with a vigorous contralateral rotation in SNR-lesioned rats. The unexpected opposite rotation after apomorphine and d-amphetamine, observed only in SNR-lesioned animals, indicates that the role of SNR in basal ganglia functions is less clear and more complex than what is expected from our current model of basal ganglia circuitry and functions. On the other hand, the GP lesion resulted in a consistent and predictable ipsilateral rotation after both apomorphine and d-amphetamine, indicating a more determinant effect on the output of the basal ganglia than heretofore believed. Our results may contribute to the recently expressed views challenging the established model of basal ganglia organisation.

Excitotoxic lateral pallidotomy does not relieve L-dopa-induced dyskinesia in MPTP parkinsonian monkeys.

We attempted to relieve the marked overactivity known to occur in the lateral segment of the globus pallidus (GPL) in L-DOPA-induced dyskinesia (LID) by unilateral stereotaxic ibotenic acid lesioning of the GPL in 4 monkeys with MPTP-induced parkinsonism. Two already dyskinetic animals were pallidotomized to counteract LID once established, while 2 L-DOPA-naive MPTP-treated animals were pallidotomized before L-DOPA was ever administered in an attempt to prevent the development of the process conductive to LID. Acutely after the lesion, more prominent akinesia (particularly in the contralateral limbs) with contraversive body deviation and circling behavior were seen for 48 h. Flexor posturing of the contralateral forelimb persisted to a variable degree. When L-DOPA treatment was resumed or instituted 1 week postoperatively, ipsiversive circling behavior occurred in all animals and contralateral dyskinesia worsened in 3, whether L-DOPA or a selective dopamine D2 agonist was administered. Lesions in these 3 cases were fairly restricted to the GPL histologically. One monkey kept L-DOPA-naive before pallidotomy never developed LID contralaterally to the lesion despite treatment for several months. The lesion this time involved the entire GP. The fact that ablation of the GPL worsened LID suggests that a complex rearrangement of the balance of functional capacity between the GP and the subthalamic nucleus takes place in LID which is not amenable to correction merely by a lateral pallidotomy. Our observations also suggest that functional redundancy exists in striatopallidal circuits and that no single pathway is responsible for LID.

Dyskinesias and tolerance induced by chronic treatment with a D1 agonist administered in pulsatile or continuous mode do not correlate with changes of putaminal D1 receptors in drug-naive MPTP monkeys.

Nine monkeys (Macaca fascicularis) were rendered parkinsonian after intravenous administration of the toxin MPTP. Three of these animals received pulsatile administration of the D1 receptor agonist SKF 82958 (1 mg/kg, three times daily) while three were treated by continuous infusion via an osmotic mini-pump with SKF 82958 (at an equivalent amount daily) for 29 days. Untreated MPTP as well as healthy control animals were also studied. Relief of parkinsonian symptoms was observed in the three animals of the pulsatile group. However, dyskinesia occurred in two monkeys which had striatal dopamine depletion of > 99% compared to the non-dyskinetic animal slightly less denervated (94%). Monkeys receiving continuous SKF 82958 showed no anti-parkinsonian effect and no dyskinesia. All monkeys from the pulsatile and continuous group had measurable amount of plasma SKF 82958 as assayed by HPLC with electrochemical detection. In the putamen of all SKF 82958-treated monkeys, Bmax of D1 receptors labeled with [3H]SCH 23390 were increased versus untreated MPTP-monkeys with no change in Kd. In contrast, a decrease D1 receptor density was observed in the nucleus accumbens of untreated MPTP monkeys versus controls and this was not corrected with either pulsatile or continuous SKF 82958 treatments. D2 receptor density measured with [3H]spiperone binding was increased in the posterior putamen of SKF 82958-treated monkeys whereas no change was observed in the accumbens compared to control animals. Hence, tolerance with the continuous administration of a D1 agonist is not associated with a decrease of putaminal D1 or D2 receptor densities and dyskinesia could not be specifically associated with an increase of putaminal D1 receptors.

Levodopa or D2 agonist induced dyskinesia in MPTP monkeys: correlation with changes in dopamine and GABAA receptors in the striatopallidal complex.

Dopamine D1 and D2 receptors as well as the GABA/benzodiazepine receptor complex in the striatum and the globus pallidus (internal: GPi and external: GPe) were studied by autoradiography using [3H]SCH 23390, [3H]spiperone, and [3H]flunitrazepam ([3H]FNZ) respectively, in five groups of cynomolgus monkeys. These included (i) untreated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-monkeys; (ii) MPTP monkeys treated chronically with levodopa injections; (iii) MPTP monkeys treated chronically with injections of the novel D2 agonist U91356A; (iv) MPTP monkeys treated chronically with U91356A delivered through an osmotic mini-pump; and (5) naive controls. Animals treated in a pulsatile mode with U91356A or levodopa injections showed progressive sensitization to their respective drug and developed choreic dyskinesia. In contrast, animals treated in a continuous mode with U91356A showed behavioral tolerance but did not develop dyskinesia. A trend for a down-regulation of putaminal D2 receptors was observed following D2 agonist stimulation with U913356A. Striatal [3H]FNZ binding was significantly decreased only in animals treated in a continuous mode with U91356A. The dopamine receptor decrease in the striatum could be implicated with the development of tolerance but cannot explain the appearance of dyskinesia. Denervation by MPTP was associated with a decrease of the GPe/GPi [3H]FNZ binding ratio which reflects an imbalance of striatal output pathways; this ratio was not reversed by any of the treatments although changes were observed in the GPe and GPi. Indeed, pulsatile U91356A treatment restored the decreased [3H]FNZ binding in the GPe near control values and levodopa showed a similar tendency. A significant increase of [3H]FNZ binding in the GPi only of dyskinetic monkeys, namely those treated with pulsatile U91356A or levodopa was seen compared to untreated MPTP or naive controls. This GABAA receptor up-regulation might lead to a supersensitive state of the GPi to gabaergic input which may be involved in the mechanism underlying the development of dopaminomimetic-induced dyskinesia.

Dopamine D1 receptor desensitization profile in MPTP-lesioned primates.

The motor effects of dopamine D1 receptor activation and the optimal way to stimulate these receptors were studied in a primate model of parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), using 2 selective full dopamine D1 receptor agonists: A-77636 ([1 R,3S] 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1 H-2-benzopyran hydrochloride), and SKF 82958 (6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrobromide). A-77636 was administered to one group of primed monkeys (N = 4) previously treated with levodopa and other dopamine receptor agonists, while SKF 82958 was given to another group of drug-naive monkeys (N = 3). These drugs have different durations of efficacy, lasting > 20 h and approximately 1 h, respectively, and were administered once daily (A-77636) or thrice daily (SKF 82958) for 7 days. Both drugs demonstrated excellent antiparkinsonian efficacy and locomotor stimulation. However, a rapid, functionally important, homologous (selective for D1 receptor agonists) desensitization process took place as early as on the second day with the longer-acting drug and a dose escalation of A-77636 failed to restore the initial benefit. Thrice daily dosing at a 4-h interval with the short-acting agent SKF 82958 maintained the maximal antiparkinsonian response but some shortening in the duration of response was observed after several days. These behavioral results show that dopamine D1 receptors are susceptible to desensitization after prolonged occupancy and can be desensitized profoundly and independently of dopamine D2 receptors in vivo in this model. Potent dopamine D1 receptor agonists with an intermediate half-life may prove to be better adjuncts in the treatment of Parkinson's disease. Clinical entities with pathologically enhanced dopamine D1 receptor-linked neural transmission might eventually also benefit from such desensitization.

The D-1 dopamine receptor: past, present and future an idiosyncratic review.

1. Key events in the experimental investigation of the D-1 dopamine receptor are reviewed. 2. The efficacy of D-1 receptor agonists in the treatment of experimental parkinsonism in MPTP-treated primates is demonstrated. The diminished dyskinetic liability of D-1 agonists is discussed. 3. The significance of the dopa-induced dyskinesias is discussed from the perspective of deterministic chaos. The unpredictibility and irreproducibility of dyskinetic movements is highlighted and compared with features of the logistic equation. 4. The authors propose that the dopa-induced dyskinesias should be considered to be a manifestation of a chaotic process within the basal ganglia. The loss of the dopaminergic innervation and the subsequent repeated exposure to dopamine (derived from the exogenous dopa administered to the subjects) alters the response properties of the basal ganglia circuitry so that stimulation of dopamine receptors now elicits the dyskinetic movements.

DOPA-induced "peak dose" dyskinesia: clues implicating D2 receptor-mediated mechanisms using dopaminergic agonists in MPTP monkeys.

Dopa-induced "peak dose" dyskinesia (DID) observed during the treatment of Parkinson's disease patients has traditionally been linked primarily to dopamine D1 receptor-mediated mechanisms. However, in MPTP-induced parkinsonian monkeys with DID, the administration of selective dopamine D1 or D2 agonists will, in the case of D1 agonists result in similar antiparkinsonian effect but with much less dyskinesia. Thus, once primed, enhanced D1 neural transmission might in fact benefit DID. In drug-naive MPTP monkeys, the high dyskinetic potential of several selective D2 agonists and the more favorable outcome on dyskinesia resulting from the continuous stimulation of D2 receptors (leading to D2 receptor down regulation) are important clues suggesting the primary role played by D2 receptor-mediated mechanisms in the dyskinesia priming process. Further clinical studies using drugs selective for the various dopamine receptor subtypes and of different efficacy half-lives are needed to validate our primate data.

Is striatal dopaminergic receptor imbalance responsible for levodopa-induced dyskinesia?

Abnormal involuntary movements (dyskinesias) of variable intensity eventually emerge in the majority of Parkinson's disease patients chronically treated with standard oral levodopa. They create social and physical embarrassment and narrow the therapeutic options normally proposed to improve Parkinsonian symptoms. Thus far, indirect clinical and experimental evidence has implicated the potential role of dopamine D1 receptor activation in the generation of dopa dyskinesia. In recent years, our group has tested several dopaminergic agonists of variable half-life and selectivity in monkeys rendered parkinsonian following toxic exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These monkeys readily develop dyskinesia when treated with levodopa and provide the best animal model to study this complication. Our results in "drug-naive" and "dyskinesia-primed" MPTP animals suggest that pathological sensitisation of D2 receptor-mediated striatal outflow is necessary and sufficient for the induction of dopa dyskinesia, with perhaps a synergistic contribution from D1 receptors, and that repeated short-lived stimulation is important in the sensitisation process. This model supports the hypothesis that more continuous forms of dopaminomimetic therapy represent the best therapeutic approach for Parkinson's disease and calls for the development of novel D1 agonists for further clinical testing.

Double-blind, crossover, placebo-controlled trial of bromocriptine in patients with sleep bruxism.

This study was designed to assess the effects of bromocriptine, a dopamine D2 receptor agonist, on sleep bruxism. Seven otherwise healthy patients with severe and frequent sleep bruxism participated in this randomized, double-blind, placebo-controlled study. The study used a crossover design that included 2 weeks of active treatment or placebo with a washout period of 1 week. To further evaluate whether bromocriptine influences striatal D2 receptor binding, we used iodine-123-iodobenzamide single photon emission computed tomography (SPECT) under both placebo and bromocriptine regimens. Bromocriptine did not reduce the frequency of episodes of bruxism during sleep (mean +/- SEM, 9.0 +/- 1.0 and 9.6 +/- 1.5 bruxism episodes per hour for placebo and bromocriptine, respectively) or the amplitude of masseter muscle contractions (root mean square values, 48.2 +/- 15.5 microV and 46.9 +/- 12.7 microV for placebo and bromocriptine, respectively). SPECT also failed to reveal that either treatment had any influence on striatal D2 binding (values for total binding in counts/pixel, 1.80 [1.72-1.93] and 1.79 [1.56-1.87] for placebo and bromocriptine, respectively). This study shows that a nightly dose of bromocriptine does not exacerbate or reduce sleep bruxism motor activity.